Identification of the Molecular Determinants Involved in Antimicrobial Activity of Pseudodesmin A, a Cyclic Lipopeptide From the Viscosin Group.
Cyclic lipo(depsi)peptides (CLiPs) from Pseudomonas constitute a class of natural products involved in a broad range of biological functions for their producers. They also display interesting antimicrobial potential including activity against Gram-positive bacteria. Literature has indicated that these compounds can induce membrane permeabilization, possibly through pore-formation, leading to the general view that the cellular membrane constitutes the primary target in their mode of action. In support of this view, we previously demonstrated that the enantiomer of pseudodesmin A, a member of the viscosin group of CLiPs, shows identical activity against a test panel of six Gram-positive bacterial strains. Here, a previously developed total organic synthesis route is used and partly adapted to generate 20 novel pseudodesmin A analogs in an effort to derive links between molecular constitution, structure and activity. From these, the importance of a macrocycle closed by an ester bond as well as a critical length of β-OH fatty acid chain capping the N-terminus is conclusively demonstrated, providing further evidence for the importance of peptide-membrane interactions in the mode of action. Moreover, an alanine scan is used to unearth the contribution of specific amino acid residues to biological activity. Subsequent interpretation in terms of a structural model describing the location and orientation of pseudodesmin A in a membrane environment, allows first insight in the peptide-membrane interactions involved. The biological screening also identified residue positions that appear less sensitive to conservative modifications, allowing the introduction of a non-perturbing tryptophan residue which will pave the way toward biophysical studies using fluorescence spectroscopy.


Drug development: Lessons from nature.
Natural products have been acknowledged for numerous years as a vital source of active ingredients in therapeutic agents. In particular, the use of active ingredients derived from plants for use in microbial natural products have long been used before the dawn of modern medicine. From ancient times, the efficacy of natural products has been associated with the chemistry, biochemistry and synthetic activities of natural products. Thus, with scientific advancement in modern molecular and cellular biology, analytical chemistry and pharmacology, the unique properties of these natural products are being harnessed in order to exploit the chemical and structural diversity and biodiversity of these types of products in relation to their therapeutic effect. Often, new molecules of interest in drug design units focus on the rearrangement of chemical entities or structural isomers of naturally occurring products in order to generate new molecules; these may be formulated into clinically useful therapies.


HSP90--news from the front.
The 90 kDa heat shock protein Hsp90 is a highly conserved and very abundant protein in the cytosol of both eukaryotic and prokaryotic cells. The main focus in the recent years has been concerned Hsp90's interaction with untransformed steroid receptors and newly synthesized kinases. Within these heterocomplexes, Hsp90 acts in concert with several other heat shock and non heat shock proteins to mediate important regulatory effects. These roles of Hsp90 leave unexplained its high abundance and heat shock regulation. More recently, however, Hsp90 has been identified as an ATP independent molecular chaperone, which binds transiently to folding intermediates in vitro, prevents aggregation and supports the refolding of the intermediates to the native state. The finding that Hsp90 interacts with late, probably highly structured, folding intermediates led to the suggestion that Hsp90 might function as a general chaperone for well structured not yet native polypeptides. This explanation provides the missing link between Hsp90 on the one hand as a highly specialized binding protein and Hsp90 on the other hand as a rather promiscuous molecular chaperone.


Matrix metalloproteinase 14 in the zebrafish: an eye on retinal and retinotectal development.
Matrix metalloproteinases (MMPs) are members of the metzincin superfamily of proteinases that cleave structural elements of the extracellular matrix and many molecules involved in signal transduction. Although there is evidence that MMPs promote the proper development of retinotectal projections, the nature and working mechanisms of specific MMPs in retinal development remain to be elucidated. Here, we report a role for zebrafish Mmp14a, one of the two zebrafish paralogs of human MMP14, in retinal neurogenesis and retinotectal development. Whole mount in situ hybridization and immunohistochemical stainings for Mmp14a in developing zebrafish embryos reveal expression in the optic tectum, in the optic nerve and in defined retinal cell populations, including retinal ganglion cells (RGCs). Furthermore, Mmp14a loss-of-function results in perturbed retinoblast cell cycle kinetics and consequently, in a delayed retinal neurogenesis, differentiation and lamination. These Mmp14a-dependent retinal defects lead to microphthalmia and a significantly reduced innervation of the optic tectum (OT) by RGC axons. Mmp14b, on the contrary, does not appear to alter retinal neurogenesis or OT innervation. As mammalian MMP14 is known to act as an efficient MMP2-activator, we also explored and found a functional link and a possible co-involvement of Mmp2 and Mmp14a in zebrafish retinotectal development. Both the Mmp14a expression in the developing visual system and the Mmp14a loss-of-function phenotype illustrate a critical role for Mmp14a activity in retinal and retinotectal development.


Membranous obstruction of the inferior vena cava: an ultrasound, computed tomography, and inferior vena cavogram image correlation.
The purpose of this paper is to present the computed tomography (CT) and ultrasound findings in one case of membranous obstruction of the inferior vena cava (IVC). Although the incidence of membranous obstruction of the IVC is rare in the United States, the diagnosis is essential because of the association of this lesion with portal fibrosis and hepatocellular carcinoma. Membranous obstruction of the IVC is suggested by the findings of a filling defect within the IVC at the level of either the diaphragm or right atrium. Until more specific CT and ultrasound features are described, an inferior vena cavogram will remain the definitive diagnostic procedure for membranous obstruction of the IVC.


[VIPoma : a rare etiology of diarrhea with hypokalemia].
VIPoma or Verner Morrison syndrome is a very rare disease with an incidence rate of 1 case per 10 000 000 person-years. It is a neuroendocrine tumor issue from β-pancreatic islets leading to profuse diarrhea, hypokalemia and gastric achlorydria due to secretion of vasoactive intestinal polypeptide (VIP) hormone. Diagnosis is based on histology of tumor and the dosage of VIP in a blood sample. Somatostatin analog is a simple and efficient treatment for diarrhea. Curative treatment with surgery could be proposed for a localized disease. For disseminated disease, there are different treatments and a multimodal assessment that should be discussed in a multidisciplinary team might be curative.


Successful therapy of retroperitoneal fibrosis due to IgG4-related disease with rituximab, cyclophosphamide and glucocorticoids followed by maintenance therapy wit ritutixmab.
Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of a peri-aortic and peri-iliac tissue showing chronic inflammatory infiltrates and pronounced fibrosis. Ureteral entrapment with consequent obstructive uropathy is one of the most common complications, which can lead to acute renal failure and, in the long term, to varying degrees of chronic kidney disease. Common symptoms at onset include lower back, abdominal or flank pain, and constitutional symptoms such as malaise, fever, and anorexia and weight loss. Pain is frequently referred to the hip, to the groin and to the lateral regions of the leg, with nocturnal exacerbations, and typically does not modify with position. We report a case of 56 year-old male with recurrent lower back pain and lower abdominal pain. Contrast-enhanced computed tomography and was suggestive of retroperitoneal fibrosis and unilateral ureteral occlusion. Histologic examination with immunohistochemical staining for IgG4 demonstrate IgG4-related retroperitoneal fibrosis. Therapy was started with prednison 1 mg/kg, but the tolerance of this dose was poor. Therefore the therapy was switched to combination of rituximab 375 mg/ m2 on day 1, cyclophosphamide 300 mg/m2 mg infusion and dexamethasone 20 mg total dose infusion on day 1 and 15 in 28 days cycle. FDG-PET/CT control in fourth month showed residual accumulation of FDG in retroperitoneal fibrotic mass, and therefore the therapy was prolonged to 8 month. The subjective symptoms of this diseases disappeared in the 8th month. Then the maintenance therapy, administration of rituximab in 6 month interval, was started. The activity of this disease be further evaluated by FDG-PET/CT imagination. Glucocorticoids are considered the cornerstone of therapy. The use of other immunosuppressive agents, including cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil and biological agents such as rituximab, tocilizumab and infliximab and sirolimus have been reported as a valuable option mostly in case reports, cases series and small studies. This agents allowed to reduce cumulative dose of glucocorticoids and its adverse effects. Therefore in our patients we preferred combination of rituximab cyclophosphamide s dexamethasone with lover dose of prednisonem. This combination is preferable for patients who cannot tolerate glucocorticoids or who are likely to suffer from significant glucocorticoids -related toxicity.


Emergence of community-associated methicillin-resistant Staphylococcus aureus infection among patients with end-stage renal disease.
To evaluate the frequency of infections due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains among our patients with end-stage renal disease. Prospective observational clinical and laboratory study of patients in 2005. Molecular features of isolates recovered from these patients were compared with those of isolates recovered in 2000 from patients with end-stage renal disease. A 600-bed urban academic medical center. Thirty-two patients with end-stage renal disease and MRSA infection at the time of hospitalization from 2005 were evaluated. For comparison, laboratory analysis was performed for 17 MRSA isolates recovered from patients with end-stage renal disease in 2000. The patients from 2005 were more likely than the patients from 2000 to have infection with strains that carried the staphylococcal cassette chromosome (SCC) mec type IV complex (50% vs 11.8%; relative risk, 4.25 [95% confidence interval, 1.17-25.98]; P = .012) and the Panton-Valentine leukocidin toxin genes (25% vs 0%; P = .038). Eight patients from 2005 were infected with a strain that is identical to MRSA clone USA300 in terms of molecular type and presence of SCCmec type IV and Panton-Valentine leukocidin genes. Among the patients from 2005, those infected with SCCmec type IV strains (ie, CA-MRSA strains) and those infected with SCCmec type II strains (ie, healthcare-associated MRSA [HA-MRSA] strains) were similar with respect to demographic characteristics, risk factors, and outcomes. We documented an increased proportion of infections with CA-MRSA strains, including clone USA300, among our population of patients undergoing dialysis. Patients infected with CA-MRSA strains and HA-MRSA strains were similar with respect to presenting illness and outcomes.


Arbuscular mycorrhizal fungi in a mountain grassland II: Seasonal variation of colonization studied, along with its relation to grazing and metabolic host type.
The relationships among seasons, host metabolic type, grazing and arbuscular mycorrhizal colonization were analyzed in a high South American native grassland. This study investigated seasonal changes and grazing effects on the symbiotic endomycorrhizal interaction in 5 Poaceae [C(3) metabolic pathway: Briza subaristata Lam., Deyeuxia hieronymi (Hack.) Türpe and Poa stuckertii (Hack.) Parodi; with C(4) metabolic pathway: Eragrostis lugens Nees and Sorghastrum pellitum (Hack.) Parodi; and a Rosaceae (Alchemilla pinnata Ruíz & Pav.)]. All hosts were dominant species in the mountain grassland in central Argentina. It was found that the seasons markedly influenced endomycorrhizal colonization, whereas grazing did not affect this interaction. C(4) grasses presented the highest root colonization. Hosts Briza subaristata (C(3) metabolic pathway) and Sorghastrum pellitum (C(4) metabolic pathway) showed Arum- and Paris-type colonization and intermediate forms.


Management of developmental asymmetrical facial growth.
Several aspects of the management of developmental asymmetrical facial growth are addressed. The abnormality is further defined. Methods of examination and assessment of records are discussed. A complicating factor has been the adoption of too many classification systems. With three-dimensional imaging techniques (computed tomography scan and stereophotography) great advancement has been made in efforts at describing the range of variation. Hemifacial microsomia patients are best treated in multidisciplinary centers by competent specialists with the necessary expertise and skills. The procedure followed in the craniofacial center in Rotterdam is described and discussed in relation to current treatment strategies. The success of the treatment of the asymmetrical facial growth depends on the original abnormality, on secondary abnormal development, and on orthodontic and surgical intervention. International cooperation is necessary to compile sufficient statistical data for a scientific evaluation of treatment results and to improve the effectiveness and the efficiency of treatment.


Photovoltage mechanism for room light conversion of citrate stabilized silver nanocrystal seeds to large nanoprisms.
We investigate the photoconversion of aqueous 8 nm Ag nanocrystal seeds into 70 nm single crystal plate nanoprisms. The process relies on the excitation of Ag surface plasmons. The process requires dioxygen, and the transformation rate is first-order in seed concentration. Although citrate is necessary for the conversion, and is consumed, the transformation rate is independent of citrate concentration. We propose a mechanism that accounts for these features by coupling the oxidative etching of the seed and the subsequent photoreduction of aqueous Ag(+). The reduced Ag deposits onto a Ag prism of specific size that has a cathodic photovoltage resulting from plasmon "hot hole" citrate photo-oxidation. This photovoltage mechanism also explains recent experimental results involving single and dual wavelength irradiation and the core/shell synthesis of Ag layers on Au seeds.


Mutation Analysis of Families with Autosomal Dominant Congenital Cataract: A Recurrent Mutation in the CRYBA1/A3 Gene Causing Congenital Nuclear Cataract.
To identify the CRYBA1/A3 mutation spectrum and analyze the genotype-phenotype correlations in Chinese families with congenital cataract. Family history and clinical data of 47 unrelated families with autosomal dominant congenital cataract (ADCC) were recorded. CRYBA1/A3 gene sequencing was applied to identify the causative mutation. Haplotypes were constructed using closely linked microsatellite markers and intragenic single-nucleotide polymorphisms (SNPs) to compare the affected haplotype in three families. Nuclear cataract was the most common type of ADCC in Chinese families, accounting for 42.6% (20/47). A recurrent CRYBA1/A3 deletion mutation (ΔG91) was identified in three families (6.4%) with nonprogressive nuclear congenital cataract. Different haplotypes segregated with the mutation in each family. A recurrent ΔG91CRYBA1/A3 mutation occurs independently in 6.4% of the Chinese families with autosomal dominant nuclear cataracts and most likely represents a mutational hot spot, which underscores the relations between nonprogressive nuclear cataract and CRYBA1/A3.


Continuous renal replacement therapy circuit failure after antidote administration.
A 73-year-old man was transferred to the emergency department (ED). He was found unconscious in his house along with an empty 200-mL bottle of Basta(™), a herbicide containing 18% glufosinate. He was comatose with a Glasgow Coma Scale score of 3. As his blood pressure dropped to 60/30 mmHg despite fluids and norepinephrine, 20% intravenous fat emulsion product was injected. He experienced repeated cardiopulmonary arrests during his first 4 h in the ED. When the arrests occurred, standard cardiopulmonary resuscitation was performed, and boluses of fat emulsion were given. He was given a total of 1500 mL of 20% fat emulsion. In an attempt to correct the acidosis, continuous renal replacement therapy (CRRT) was started. Within 5 min of starting CRRT, the transmembrane pressure increased sharply and the machine stopped.


Oxidative lesion to membrane proteins in senescent erythrocytes.
The oxidative lesion undergone by membrane proteins in senescent human erythrocytes was evaluated by assaying their MetSO and thiol group content in ghosts and the amount of a coumarinyl derivative of maleimide, the DACM, bound by individual membrane proteins after treatment of erythrocytes of different age with this reagent. Quantitation of MetSO content of ghost membranes indicates an increase of the oxidative state of membrane proteins from young to mature and senescent erythrocytes, while thiol group assay does not show significant differences among erythrocytes of different age. Quantitation of DACM bound in intact cells by individual membrane proteins shows a decreased accessibility of thiol groups of band 3 protein and of the main proteins of the membrane skeleton in senescent erythrocytes, and this could be partly due to oxidation. The decreased reactivity to DACM of senescent erythrocyte band 3 seems to concern thiols located on the cytoplasmic domain of this protein, since the anion channel binds the same amount of the anion transport inhibitor EM, in mature and senescent erythrocytes.


Nutritional ecology of obesity: from humans to companion animals.
We apply nutritional geometry, a framework for modelling the interactive effects of nutrients on animals, to help understand the role of modern environments in the obesity pandemic. Evidence suggests that humans regulate the intake of protein energy (PE) more strongly than non-protein energy (nPE), and consequently will over- and under-ingest nPE on diets with low or high PE, respectively. This pattern of macronutrient regulation has led to the protein leverage hypothesis, which proposes that the rise in obesity has been caused partly by a shift towards diets with reduced PE:nPE ratios relative to the set point for protein regulation. We discuss potential causes of this mismatch, including environmentally induced reductions in the protein density of the human diet and factors that might increase the regulatory set point for protein and hence exacerbate protein leverage. Economics--the high price of protein compared with fats and carbohydrates--is one factor that might contribute to the reduction of dietary protein concentrations. The possibility that rising atmospheric CO₂ levels could also play a role through reducing the PE:nPE ratios in plants and animals in the human food chain is discussed. Factors that reduce protein efficiency, for example by increasing the use of ingested amino acids in energy metabolism (hepatic gluconeogenesis), are highlighted as potential drivers of increased set points for protein regulation. We recommend that a similar approach is taken to understand the rise of obesity in other species, and identify some key gaps in the understanding of nutrient regulation in companion animals.


Leaf removal at veraison stage differentially affects qualitative attributes and bioactive composition of fresh and dehydrated grapes of two indigenous Cypriot cultivars.
The effect of leaf removal on postharvest performance of dehydrated grapes has been poorly analyzed. The aim of this study was to evaluate the effect of leaf removal at veraison stage on the metabolites of fresh and dehydrated grapes of two indigenous Cypriot cultivars ('Mavro' and 'Xynisteri'), which are destined for the production of 'Commandaria', a protected designation of origin (PDO) premium sweet wine. Leaf removal led to a reduction of soluble solids, titratable acidity, aroma potential and most of the phenolic groups in the musts of both cultivars. Dehydration led to a significant increase in all of these parameters in both cultivars, being more pronounced in cv. 'Mavro'. Interestingly, leaf removal indicated differential response in the dehydrated product of the cultivars examined; liquid chromatography (LC-DAD-qTOF-MS) data showed a significant decrease in phenolic compounds in 'Xynisteri' must (from 66.73 to 44.15 mg L-1 ), while 'Mavro' must registered similar values of phenolic compounds (from 94.78 to 96.72 mg L-1 ), but with a different distribution among phenolic groups. Intriguingly, flavonols and flavan-3-ols that present significant health-promoting properties showed higher concentrations in the must from dehydrated 'Mavro' grapes that were subjected to preharvest leaf removal. Leaf removal at veraison stage followed by sun drying differentially affected the chemical composition of the examined cultivars. This preharvest application followed by postharvest dehydration was beneficial for cv. 'Mavro', while this was not the case for cv. 'Xynisteri'. The effects of leaf removal in other developmental stages (i.e. pre/post bloom stage) need to be dissected with the ultimate goal of providing an end product with high bioactive content. © 2018 Society of Chemical Industry.


Jejunal access loop cholangiogram and intervention using image guided access.
Jejunal access loop is fashioned in patients who undergo Roux en Y hepaticojejunostomy and biliary intervention is anticipated on follow up. Post-operative study of the biliary tree through the access loop is usually done under fluoroscopic guidance. We present a series of 20 access loop cholangiograms performed in our institution between August 2004 and November 2008. We aimed to evaluate the safety and efficacy of the procedure and to highlight the role of CT guidance in procuring access. Access loop was accessed using CT (n = 13), ultrasound (n = 3) or fluoroscopic guidance (n = 4). Fluoroscopy was used for performing cholangiograms and interventions. Twelve studies had balloon plasty of the stricture at anastomotic site or high up in the hepatic ducts. Seven studies showed normal cholangiogram. Plasty was unsuccessful in one study. Technical success in accessing the jejunal access loop was 100%; in cannulation of anastomotic site and balloon plasty it was 95%. One case required two attempts. Procedure-related complications were not seen. All patients who underwent balloon plasty of the stricture were doing well for variable lengths of time. Access loop cholangiogram and interventions are safe and effective. CT guidance in locating/procuring the access loop is a good technique.


Management of prosthetic abutments respecting peri-implant soft tissues.
Periodontal and peri-implant soft tissues are very similar in many aspects (phenotype, mucosal dimensions, biological width). In peri-implant tissue, the mucosal seal is localized apically to the gap existing between the fixture and the prosthetic abutment. This is due to mechanical trauma created by screwing and unscrewing the prosthetic components, to mechanical deformation produced under functional stress and to bacterial colonization. To reduce the effects of this gap on peri-implant soft tissues stability several options are available: supracresta fixture positioning, reduction of the fixture-abutment gap, and minimizing the prosthetic steps. A clinical case was illustrated. Abutments (Gingi-hue 3I with a fixture-abutment gap less than 2 mm and a fixture abutment angle rotation of 0.4 degrees ) were screwed on the fixtures after the second stage surgery and used as impression transfer. These abutments were prepared in the laboratory and definitively screwed after the impression session. The use of definitive abutments as transfer reduces the session number and allows the peri-implant soft tissues to heal without beeing troubled by screwing and unscrewing of the prosthetic components.


[Spinal wedged osteotomy combined with total hip arthroplasty for kyphosis and severe hip flextion contracture caused by ankylosing spondylitis].
To evaluate the effectiveness of spinal wedged osteotomy and total hip arthroplasty (THA) for treatment of kyphosis and severe hip flexion contracture caused by ankylosing spondylitis (AS). Between December 2008 and November 2011, 25 patients (37 hips) with kyphosis and severe hip flexion contracture caused by AS were treated. There were 22 males and 3 females, aged 29-38 years (mean, 35.6 years). The disease duration was 8-16 years (mean, 13.2 years). Of them, 18 cases had complete limitation of hip motion, and 16 cases had severe spine deformity (Cobb's angel ≥ 60 degrees). All 25 cases underwent spinal wedged osteotomy at first, and then received THA after 8 weeks. The effectiveness was evaluated by Harris hip score, range of motion (ROM) of the hip, visual analogue scale (VAS) score, Cobb's angle, and information and data exchange system (IDES) criteria for aseptic loosening, respectively. The patients were followed up 12-14 months (mean, 13 months). Spondylolisthesis (II degree) occurred in 1 case spinal after wedged osteotomy, and was corrected after second operation. No vascular injury or spinal cord injury was observed. Bony fusion was obtained at osteotomy ends at 6 months after operation. The Cobb's angle was significantly corrected from (83.5 ± 10.4)degrees preoperatively to (25.4 ±. 5.5)degrees (t = 24.63, P = 0.00) 12 months postoperatively. One case had traction injury of the femoral nerve after THA, and the muscle function recovered at 9 months after operation. According to IDES criteria, up-displacement of cup (< 5 mm) was observed in 1 patient, who had no obvious clinical symptoms; periacetabular osteolysis occurred in 1 patient, with no displacement of cup. No obvious radiolucent was seen in 37 hips. The Harris hip score was significantly improved from (26.87 ± 4.23) preoperatively to 85.92 ± 6.04) (t = 28.72, P = 0.00) 3 months postoperatively; the VAS score was significantly decreased from (6.71 ± 1.14) preoperatively to (2.31 ± 0.82)(t = 42.26, P = 0.00) 3 months postoperatively; and the flexion-extension ROM of the hip was significantly improved to 60-100 degrees (mean, 72.0 degrees) at post-operation, and the abduction ROM of the hip was improved to 20-40 degrees (mean, 28.7 degrees). Spinal wedged osteotomy combined with THA is an efficient treatment for kyphosis and severe hip flexion contracture caused by AS.


The Extent of Heavy Metal Pollution and Their Potential Health Risk in Topsoils of the Massively Urbanized District of Shanghai.
Urbanization and industrialization increase the concentrations of heavy metals in soils, which affect human health. A total of 127 topsoil samples were collected from the massively urbanized and industrialized district of Shanghai: Baoshan District. The sampling sites were isolated based on the land-use practice: industrial area, roadside area, residential area, and agricultural area. The absolute concentrations of heavy metals (Zn, Cr, Ni, Mn, Cu, Pb, and Cd) were determined using atomic absorption spectrometry and compared with Shanghai and the National soil background values. The geoaccumulation index (Igeo) and Nemerow pollution index were used to determine the existence and severity of the pollution of heavy metals. Enrichment factor (EF) analysis, spatial variability of pollution, and multivariate statistical analyses also were employed to determine the anthropogenic loading of heavy metals, their spatial dependency, and correlation among their sources, respectively. Moreover, potential ecological risk and human health risk [carcinogenic risk (RI) and noncarcinogenic hazard (HI)] were evaluated. The average concentration of all the metals (accounted as 229, 128, 56, 719, 55, 119, and 0.3 mg kg-1 for Zn, Cr, Ni, Mn, Cu, Pb, and Cd, respectively) was many folds higher than the background values. The indices depicted that the pollution exists in all the sites and severity decreases in the following order: industrial soils > roadside soil > residential soils > agricultural soils. However, Zn, Pb, and Cd showed high levels of pollution in all the soils. The EF values suggested that the majority of heavy metals are anthropogenically loaded; spatial variability showed that the pollution is more concentrated in Songnan town; Pearson's correlation, principal component analysis (PCA), and cluster analysis suggested different sources of origin for the majority of the heavy metals. RI of Cr and Pb ranged between 2.8E-04 and 2.7E-07. However, HI was site-specific (only for Cr, Pb, Mn), and most of the sites were in Songnan town. This study could be used as a significant piece of information for management purposes to prevent heavy metal pollution and to protect human health.


Synovial Fluid Eotaxin-1 Levels May Reflect Disease Progression in Primary Knee Osteoarthritis Among Elderly Han Chinese: A Cross-Sectional Study.
The CC chemokine family member eotaxin-1, also named chemokine C-C motif ligand 11 (CCL11), has been detected in knee osteoarthritis (OA) and could induce breakdown of cartilage matrix. This study was performed to investigate the plasma and synovial fluid eotaxin-1 levels with the disease progression in elderly Han Chinese with primary knee OA. A total of 143 elderly primary knee OA patients and 135 healthy controls were enrolled in the study. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) was performed to evaluate the clinical severity. The radiographic severity was assessed by Kellgren-Lawrence (K-L) grading. Plasma and synovial fluid (SF) eotaxin-1 levels were explored using enzyme-linked immunosorbent assay. The SF levels of matrix metalloproteinase-3 (MMP-3) and interleukin-6 (IL-6) were also examined. Elevated plasma eotaxin-1 levels were found in knee OA patients compared with healthy controls. Eotaxin-1 levels in SF of knee OA patients with K-L grade 4 were significantly elevated compared with those with K-L grades 2 and 3. Meanwhile, knee OA patients with K-L grade 3 had significantly increased SF levels of eotaxin-1 compared with those with K-L grade 2. Plasma eotaxin-1 levels in different K-L grading did not reach significant difference. Eotaxin-1 levels in SF of knee OA patients were significantly associated with disease severity evaluated by KL grading criteria. In addition, eotaxin-1 levels in SF were positively related to clinical severity illustrated by WOMAC as well as biochemical markers MMP-3 and IL-6. Eotaxin-1 levels in SF instead of plasma, were independently and positively related to the disease severity in elderly knee OA patients. The inhibition of eotaxin-1 and its related signaling pathways may serve as a novel therapeutic approach for OA progression.


Impacts of impaired mitochondrial dynamics in hearing loss: Potential therapeutic targets.
Mitochondria are the powerhouse of the cells. Under physiological conditions, mitochondrial fission and fusion maintain a dynamic equilibrium in the cytoplasm, which is referred to as mitochondrial dynamics. As an important approach to regulating mitochondrial function and quantity, the role of mitochondrial dynamics has been demonstrated in the pathogenesis of various disease models, including brain damage, neurodegeneration, and stress. As the vital organ of the peripheral auditory system, the cochlea consumes a significant amount of energy, and the maintenance of mitochondrial homeostasis is essential for the cochlear auditory capacity. OPA1 functions as both a necessary gene regulating mitochondrial fusion and a pathogenic gene responsible for auditory neuropathy, suggesting that an imbalance in mitochondrial dynamics may play a critical role in hearing loss, but relevant studies are few. In this review, we summarize recent evidence regarding the role of mitochondrial dynamics in the pathogenesis of noise-induced hearing loss (NIHL), drug-induced hearing loss, hereditary hearing loss, and age-related hearing loss. The impacts of impaired mitochondrial dynamics on hearing loss are discussed, and the potential of mitochondrial dynamics for the prevention and treatment of hearing loss is considered.


Risk of development of acute pancreatitis with pre-existing diabetes: a meta-analysis.
It is well established that acute pancreatitis (AP) often causes diabetes mellitus. However, whether pre-existing diabetes is associated with the development of AP remains unknown. To clarify the association of pre-existing diabetes and the development of AP, we carried out a meta-analysis of observational studies. A computerized literature search was performed in MEDLINE (from 1 January 1966) and EMBASE (from 1 January 1974), through 31 January 2012. We also searched the reference lists of relevant articles. Summary relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I 2. A total of seven articles (10 523 incident cases of AP) were included in this meta-analysis. Analysis of seven studies indicated that, compared with nondiabetic individuals, diabetic individuals had a 92% increased risk of development of AP (95% CI 1.50-2.47). There was significant evidence of heterogeneity among these studies (P heterogeneity<0.001, I 2=93.0%). These increased risks were independent of alcohol use, gallstones, and hyperlipidemia. Although the current evidence supports a positive link between pre-existing diabetes and an increased risk of development of AP, additional studies, with a perfect design, are required before definitive conclusions can be drawn.


Picovoltmeter for probing vortex dynamics in a single weak-pinning Corbino channel.
We have developed a picovoltmeter using a Nb dc superconducting quantum interference device for measuring the flux-flow voltage from a small number of vortices moving through a submicron weak-pinning superconducting channel. We have applied this picovoltmeter to measure the vortex response in a single channel arranged in a circle on a Corbino disk geometry. The circular channel allows the vortices to follow closed orbits without encountering any sample edges, thus eliminating the influence of entry barriers.


The Potential Container Habitats of Chikungunya Vector in Outbreak Area of Southern Thailand.
Chikungunya virus (CHIKV) is primarily transmitted by Aedes mosquitoes and is responsible for reemerging disease internationally. Container habitats of immature Aedes mosquitoes are often found around residential areas, thus water-holding container investigation is an important vector control strategy. This study aimed to survey mosquito species in container inhabiting stages and water-holding containers associated with the CHIKV outbreak in urban areas within the 4 villages of Hat Yai district in Songkhla province during 2019. The results indicated that of the 75 houses surveyed, 34 had water-holding containers; 78 out of 438 containers were positive for mosquitoes; and 34 were positive for mosquito stages. The house index (HI), Breteau index (BI), container index (CI), and pupal index (PI) were 46.87, 93.75, 14.92, and 271.88 for case houses, respectively. Specific container index (SCI) showed discarded containers such as bottles, cans, and tires. The findings suggest that Aedes aegypti was predominant in the surveyed urban area and might be the vector responsible for CHIKV transmission in Songkhla province.


Quality assurance study for dosimetry of radiation therapy equipment in Saudi Arabia.
International standards address the accuracy of dose delivery for radiation therapy machines as well as quality assurance and staffing levels for radiation therapy centers. We performed absolute calibrations of gamma, x-ray and electron radiotherapy beams in all radiation therapy centers in Saudi Arabia. We also assessed quality assurance and staffing levels. Dosimetric measurements were made with a portable dosimetry system, which consisted of a calibrated Farmer ionization chamber and an electrometer, small water phantom, barometer, and thermometer. Differences between the measured and the expected output (cGy/MU or cGy/min) were found to be in the range of -11% + 5%. About 17% of the radiotherapy beams were not within the acceptable tolerance level (+/-3%). Quality assurance in some radiation therapy centers was poor and staffing levels were inadequate. We found poor compliance with internationally accepted tolerance levels for dose calibration of radiotherapy beams at radiation therapy centers in Saudi Arabia. Analysis of medical physics staffing revealed severe discrepancies from those recommended by international guidelines. We recommend that radiation therapy centers be adequately staffed with qualified medical physics personnel and that periodic audit programs be required by a governmental body.


[First fixed dose combination perindopril arginine-indapamide-amlodipine: new approach in combination therapy in hypertension].
Use of fixed combination of antihypertensive drugs clearly improves compliance to the pharmacological therapy, control of hypertension and prognosis. Based on the current guidelines triple antihypertensive therapy with RAS-blocker, calcium channel blocker (CCB) and diuretic represents the standard and best option. The article introduces first and innovative fixed triple combination of perindopril arginine + indapamide + amlodipine (Triplixam®). This type of therapy is suitable for patients already treated with free combinations of three antihypertensive drugs or in those hypertensives with uncontrolled hypertension on two antihypertensive molecules (approx. 60% of all hypertensive population). Fixed combination of perindopril arginine + indapamid + amlodipin is indicated also in severe hypertension (approx. 30% of pts). Large clinical data from various morbidity-mortality studies related to each of these substances are discussed as well as basic pharmacological characteristics. Based on the results from ADVANCE-CCB study combination of perindopril arginine + indapamide + CCB decreases total mortality in hypertension by 28%. Another discussed study-PIANIST confirmed significant antihypertensive effect of Triplixam® on large sample of patients with various stages of hypertension. Triplixam® in addition to that has very good tolerance with low side effects profile, flexibility of the dosages and large body of evidence of positive impact on prognosis of hypertensive patients. Use of Triplixam® may improve control of hypertension in the Czech Republic.Key words: amlodipine - fixed combination - hypertension - indapamide - perindopril arginine - therapy.


Organogel-nanoemulsion containing nisin and D-limonene and its antimicrobial activity.
The aim of this study was to investigate a novel delivery system containing D-limonene and nisin by food organogel-nanoemulsion and study its effect on the antimicrobial activity. Organogel-nanoemulsion containing with D-limonene and nisin or without nisin was prepared by a homogenization method. Factors that may affect the droplet size and stability of organogel-nanoemulsion such as pressure and surfactant to oil ratio (SOR) were studied. The average droplet size decreased with pressure, and the organogel-nanoemulsion could achieve good stability at low SOR. Positive effects and outstanding antimicrobial activities of organogel-nanoemulsion containing with D-limonene and nisin were confirmed by minimal inhibitory concentrations comparison, growth curves of bacteria, scanning electron microscopy and determination of cell constituents' release. Furthermore, the organogel-nanoemulsion applied as food preservative in milk also shown excellent antimicrobial performance. Overall, the research described in the current article show that organogel-nanoemulsion containing with D-limonene and nisin may be an effective antimicrobial system for the production and preservation of food.


[Effect of chronic renal failure and hemodialysis on the pancreas-specific enzyme pattern in the serum].
Amylase concentration in serum is frequently found increased in chronic renal insufficiency without being associated with pancreatic diseases. A prospective study was performed in 71 patients with chronic renal insufficiency undergoing hemodialysis for comparison of different pancreatic enzymes in serum. 7 patients were not considered in this comparative study because of chronic pancreatitis-like-changes in ultrasound. Increased serum concentrations were found for total amylase in 27 patients (42.2%), pancreatic amylase in 26 patients (25.0%), lipase in 50 patients (78.1%), immunoreactive trypsin in 61 patients (95.3%) and for elastase 1 in 7 patients (10.9%). Hemodialysis did not affect any of the investigated pancreatic serum-enzymes. Elastase 1 determination in serum appears superior to the other pancreatic serum-enzymes because of higher specificity, not limited by renal insufficiency. The different serum concentration of elastase 1 and trypsin, which have a similar molecular weight, points towards a completely different clearance mechanism for these enzymes.


High-Carbohydrate Diets and Food Patterns and Their Associations with Metabolic Disease in the Korean Population.
Although an Asian diet is typically high in carbohydrate and low in fat, there has been a steady increase in the rate of cardiometabolic disease in Asian countries over the past decade. We evaluated food patterns of a high-carbohydrate diet and examined their associations with metabolic disease. Using data from the 2013-2015 Korean National Health and Nutrition Examination Survey, we included a total of 13106 subjects aged 20 years or older in this study. Diet was divided into seven groups according to the percentage of energy from carbohydrates. Food patterns were evaluated as individual servings per food group. Multivariate logistic regression was conducted to estimate odds ratios (OR) for metabolic disease. The proportions of men and women exceeding the recommended range of carbohydrate intake were 58.0% and 60.0%, respectively. A higher carbohydrate diet was associated with intake of low energy and saturated fats, with more grains and fruit, but less meat, fish, egg, bean (MFEB), and dairy consumption. Carbohydrate intake decreased by 3.0-3.4% per serving of MFEB and milk. In men, the highest carbohydrate group showed an OR of 1.35 [95% confidence interval (CI), 0.91 to 1.99] for metabolic syndrome, although this failed to show statistical significance. In women, the highest carbohydrate group had an OR of 1.38 (95% CI, 1.06 to 1.80) for a reduced level of high-density lipoprotein cholesterol. This study suggests that a very-high-carbohydrate diet for the Korean population is attributable to lower consumption of MFEB and dairy products and is associated with several metabolic risk factors. The appropriate distribution of macronutrients for the prevention and management of metabolic disease should be explored.


Ethical aspects of the mitigation obstruction argument against climate engineering research.
Many commentators fear that climate engineering research might lead policy-makers to reduce mitigation efforts. Most of the literature on this so-called 'moral hazard' problem focuses on the prediction that climate engineering research would reduce mitigation efforts. This paper focuses on a related ethical question: Why would it be a bad thing if climate engineering research obstructed mitigation? If climate engineering promises to be effective enough, it might justify some reduction in mitigation. Climate policy portfolios involving sufficiently large or poorly planned reductions in mitigation, however, could lead to an outcome that would be worse than the portfolio that would be chosen in the absence of further climate engineering research. This paper applies three ethical perspectives to describe the kinds of portfolios that would be worse than that 'baseline portfolio'. The literature on climate engineering identifies various mechanisms that might cause policy-makers to choose these inferior portfolios, but it is difficult to know in advance whether the existence of these mechanisms means that climate engineering research really would lead to a worse outcome. In the light of that uncertainty, a precautionary approach suggests that researchers should take measures to reduce the risk of mitigation obstruction. Several such measures are suggested.


Estimated number of injection-involved drug overdose deaths, United States, 2000 - 2018.
In the United States, drug overdose mortality has increased. Death records categorize overdose deaths by type of drug involved, but do not include information about the route of drug administration. We utilized data from drug treatment admissions (Treatment Episodes Dataset, TEDS-A) and National Vital Statistics Systems to estimate the percentage of reported drug overdose deaths that were injection-involved from 2000 to 2018 in the U.S. Data on reported route of administration at admission were used to calculate the percent injecting each drug type, by demographic group (race/ethnicity, sex, age group) and year. Using the resulting probabilities, we estimated the number of overdose deaths that were injection-involved. Estimates were compared across drug types, demographic characteristics, and year. The number of overdose deaths among adults increased more than 3-fold from 2000 (n = 17,196) to 2018 (n = 67,021). During that timeframe, the number of estimated injection-involved overdose deaths increased more than 8-fold from 2000 (n = 3467, 95% CI: 3449-3485) to 2018 (n = 28,257, 95% CI: 28,192-28,322). From 2000-2007, the percent of overdose deaths that were injection-involved remained stable around 20%. From 2007-2018, the percent of overdose deaths that were injection-involved increased from 18.4% (95% CI: 18.3-18.6%) to 42.2% (95% CI: 42.1-42.3%). In 2018, most estimated injection-involved overdose deaths were due to injecting heroin/synthetic opioids (n = 24,860, 95% CI: 24,800-24,919), which accounted for 88.0% of all injection-involved deaths. Much of the recent increase in overdose mortality is likely attributable to rising injection-involved overdose deaths.


MicroRNA expression changes after lung cancer resection: a follow-up study.
MiRNAs are powerful biomarkers for detecting various diseases from tissue and body fluids. The potential of these molecules to monitor patients over time has, however, been less explored. We followed the fate of the plasma miRNome of lung cancer patients starting prior to surgery and ending 18 mo after surgery, with blood taken at three-month intervals. Principal component and clustering analysis showed that the differences of the overall miRNA patterns between the different time points were significantly smaller than between patients. For each patient we found a rather specific fluctuating miRNA pattern. We identified miRNAs that showed a significant correlation between expression level and time distance from surgery. A network analysis revealed 12 correlated miRNAs regulating 48 genes that were deregulated in lung cancer tissue. Our data underline the importance of studies that follow the fate of miRNAs over time, both to further our understanding of the biology of miRNA signatures and to establish these signatures as biomarkers.


Occupational Safety and Health and Illicit Opioids: State of the Research on Protecting Against the Threat of Occupational Exposure.
The nationwide opioid crisis continues to affect not only people who use opioids but also communities at large by increasing the risk of accidental occupational exposure to illicit opioids. In addition, the emergence of highly potent synthetic opioids such as fentanyl and carfentanil increases the need to protect workers who may encounter unknown drug substances during job activities. To support the National Institute for Occupational Safety and Health Opioids Research Gaps Working Group, we examined the state of the literature concerning methods to protect workers against accidental occupational exposure to illicit opioids, and have identified unmet research needs concerning personal protective equipment, decontamination methods, and engineering controls. Additional studies are needed to overcome gaps in technical knowledge about personal protective equipment, decontamination, and control methods, and gaps in understanding how these measures are utilized by workers. Increasing our knowledge of how to protect against exposure to illicit opioids has the potential to improve occupational health across communities.


Real-Life Data From the Largest Pediatric Familial Mediterranean Fever Cohort.
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting phenotypic heterogeneity. It is a clinically diagnosed disease supported by MEditerranean FeVer (MEFV) gene mutation analysis. However, the phenotype-genotype correlation is not yet established clearly. We aimed to determine the clinical findings, phenotype-genotype correlation, and treatment outcomes within a large pediatric FMF cohort. The medical charts of children with FMF who were diagnosed and followed up at the eight pediatric rheumatology units were reviewed retrospectively. All patients in the cohort were analyzed for sequence variants in exon 2,3,5 and 10 of the MEFV gene. Patients without any mutations or with polymorphisms including R202Q were excluded. A total of 3,454 children were involved in the study. The mean ± standard deviation of current age, age at symptom onset, and age at diagnosis were 12.1 ± 5.2, 5.1 ± 3.8, and 7.3 ± 4.0 years, respectively. Of 3,454 patients, 88.2% had abdominal pain, 86.7% had fever, 27.7% had arthritis, 20.2% had chest pain, 23% had myalgia, and 13.1% had erysipelas-like erythema. The most common MEFV mutation patterns were homozygous (32.5%) and heterozygous (29.9%) mutations of exon 10. Homozygous M694V was present in 969 patients (28.1%). Allele frequencies of common mutations were M694V (55.3%), M680I (11.3%), V726A (7.6%), and E148Q (7.2%). Children carrying homozygous or compound heterozygous exon 10 mutations had an earlier age of disease onset (4.6 vs. 5.6 years, p = 0.000) and a higher number of attacks per year (11.1 vs. 9.6, p = 0.001). Although 8% of the patients had a family history of amyloidosis, 0.3% (n = 11) had the presence of amyloidosis. M694V homozygosity was detected in nine patients who developed amyloidosis. Colchicine resistance was present in 4.2% of our patients. In this largest pediatric cohort reviewed and presented to date, patients with exon 10 mutations, particularly the M694V homozygous mutation, have been demonstrated earlier disease onset, annual attack count, and more frequent colchicine-resistant cases. Although E148Q is considered as a polymorphism in some populations, it was identified as a disease-causing mutation in our cohort. Secondary amyloidosis is still happening in adults however, it is extremely rare among children, presumably due to increased awareness, tight control, and the availability of anti-IL1 agents in colchicine-resistant cases.


[Investigation of CNTF, COMT, DDR1, DISC1, DRD2, DRD3, and DTNBP1 candidate genes in schizophrenia: Results from the Hungarian SCHIZOBANK Consortium].
Schizophrenia is a chronic, debilitating psychiatric disorder characterized by heterogeneous clinical symptoms. Although the pathogenesis of this disorder is poorly understood, several lines of evidence support the role of both common and rare genetic variants in the etiology of schizophrenia. Common variants, single nucleotide polymorphisms can be investigated by candidate gene association studies or genome-wide association studies, while rare variants, single nucleotide variants are assessable by means of candidate gene resequencing or whole-exome and genome sequencing using next generation sequencing. In this study we investigated polymorphisms of 7 candidate genes in a Hungarian schizophrenia cohort. Candidate genes were chosen on the basis of previous results and biological plausibility. 390 patients were recruited in 5 centers in the framework of the Hungarian SCHIZOBANK Consortium, the schizophrenia sample was contrasted to 1069 healthy control individuals. In this sample SNPs of DDR1 and DRD2 genes demonstrated significant association with schizophrenia. The role of DDR1 and DRD2 genes in the etiology of schizophrenia warrant further investigation, based on their genomic localization and biological functions.


A frame-relay approach for a state-wide health information network.
An approach for a frame-relay implementation is described which is intended to establish connectivity between the health care providers in the state of Connecticut with a gateway to the internet. While other health care networking efforts have based the interconnectivity efforts on direct connections to the internet for each institution, our design takes a more cost effective approach by establishing a private health care network with a single entry point to the internet. This will not only provide the advantages of internet connections to all participating providers, but it will also isolate intrastate patient care traffic from the internet, reserving internet traffic for those information needs not available within the statewide network. In addition to the network solution, an extensive user support infrastructure is also presented.


Neobladder and ablative pelvic radiotherapy: still a taboo?
The presence of a neobladder constitutes a limitation for the radiation oncologist, as there is no clear evidence about its tolerance to radiotherapy (RT). The limited literature only concerns the conventional postoperative treatment in patients with bladder cancer after cystectomy. Here we report a case of a patient with neobladder who underwent a stereotactic RT for a pelvic recurrence of disease, with response to treatment and no toxicity to the neobladder. This case represents a promising example of the chance to perform RT with ablative intent, using advanced techniques, even on lesions close to the neobladder.


Responding to COVID-19: Resilience in Occupational Therapy.
This special issue of the American Journal of Occupational Therapy highlights the contribution of occupational therapy practitioners to the care of clients during the coronavirus disease 2019 (COVID-19) pandemic. The case studies and articles exemplify the resilience of practitioners and the importance of occupational therapy interventions in addressing the physical, cognitive, psychological, and social needs of clients, their families, and care providers. We encourage practitioners to be inventive, to be collaborative, and to contribute to research regarding the benefits of occupational therapy for this population.


Of whistleblowers, investigators, and judges.
Deliberate misrepresentation continues. Needleman attacks the whistleblowers, the NIH, and his own University to deflect attention from the indications of misconduct in his research. Federal agencies base policies on his research and on his assertions regarding the purported effects of low-level lead exposure on children. The policies divert resources and attention from the real needs of children. Misconduct issues will ultimately be resolved by the ORI and the courts. Public policy issues may require reconsideration in light of further evidence.


A Co-Training Framework for Heterogeneous Heuristic Domain Adaptation.
The purpose of this article is to address unsupervised domain adaptation (UDA) where a labeled source domain and an unlabeled target domain are given. Recent advanced UDA methods attempt to remove domain-specific properties by separating domain-specific information from domain-invariant representations, which heavily rely on the designed neural network structures. Meanwhile, they do not consider class discriminate representations when learning domain-invariant representations. To this end, this article proposes a co-training framework for heterogeneous heuristic domain adaptation (CO-HHDA) to address the above issues. First, a heterogeneous heuristic network is introduced to model domain-specific characters. It allows structures of heuristic network to be different between domains to avoid underfitting or overfitting. Specially, we initialize a small structure that is shared between domains and increase a subnetwork for the domain which preserves rich specific information. Second, we propose a co-training scheme to train two classifiers, a source classifier and a target classifier, to enhance class discriminate representations. The two classifiers are designed based on domain-invariant representations, where the source classifier learns from the labeled source data, and the target classifier is trained from the generated target pseudolabeled data. The two classifiers teach each other in the training process with high-quality pseudolabeled data. Meanwhile, an adaptive threshold is presented to select reliable pseudolabels in each classifier. Empirical results on three commonly used benchmark datasets demonstrate that the proposed CO-HHDA outperforms the state-of-the-art domain adaptation methods.


A new technique for greater trochanteric hip arthroplasty.
This paper describes a new technique for greater trochanteric hip arthroplasty in which the femur is divided at the subtrochanteric level and the upper fragment rotated through 180 degrees to place the greater trochanter deeply in the acetabulum; with the lower limb in the weight-bearing position the fragments are then fixed with a short intramedullary nail. This operation was carried out in a boy aged 4 years 6 months in whom the femoral head and neck had been destroyed by septic arthritis. Ten years later leg-lengthening was performed. When reviewed at the age of 20, he had a stable hip, a satisfactory range of painless movement, and shortening of only 2.5 cm; he could walk and run for long distances with only a slight abductor lunch.


Glycine-rich transmembrane helix 10 in the staphylococcal tetracycline transporter TetA(K) lines a solvent-accessible channel.
The staphylococcal TetA(K) tetracycline exporter is classified within the major facilitator superfamily of transport proteins and contains 14 alpha-helical transmembrane segments (TMS). Using cysteine-scanning mutagenesis, 27 amino acid residues across and flanking putative TMS 10 of the TetA(K) transporter were individually replaced with cysteine. The level of solvent accessibility to each of the targeted amino acid positions was determined as a measure of fluorescein maleimide reactivity and demonstrated that TMS 10 of TetA(K) has a cytoplasmic boundary at G313 and is likely to extend from at least V298 on the periplasmic side. TMS 10 was found to be amphiphilic containing at least partially solvent accessible amino acid residues along the length of one helical face, suggesting that this helix may line a solvent-exposed channel. Functional analyses of these cysteine mutants demonstrated a significant role for a number of amino acid residues, including a predominance of glycine residues which were further analyzed by alanine substitution. These residues are postulated to allow interhelical interactions between TMS 10 and distal parts of TetA(K) that are likely to be required for the tetracycline transport mechanism in TetA(K) and may be a general feature required by bacterial tetracycline transporters for activity.


Structure of Shigella IpgB2 in complex with human RhoA: implications for the mechanism of bacterial guanine nucleotide exchange factor mimicry.
A common theme in bacterial pathogenesis is the manipulation of eukaryotic cells by targeting the cytoskeleton. This is in most cases achieved either by modifying actin, or indirectly via activation of key regulators controlling actin dynamics such as Rho-GTPases. A novel group of bacterial virulence factors termed the WXXXE family has emerged as guanine nucleotide exchange factors (GEFs) for these GTPases. The precise mechanism of nucleotide exchange, however, has remained unclear. Here we report the structure of the WXXXE-protein IpgB2 from Shigella flexneri and its complex with human RhoA. We unambiguously identify IpgB2 as a bacterial RhoA-GEF and dissect the molecular mechanism of GDP release, an essential prerequisite for GTP binding. Our observations uncover that IpgB2 induces conformational changes on RhoA mimicking DbI- but not DOCK family GEFs. We also show that dissociation of the GDP.Mg(2+) complex is preceded by the displacement of the metal ion to the alpha-phosphate of the nucleotide, diminishing its affinity to the GTPase. These data refine our understanding of the mode of action not only of WXXXE GEFs but also of mammalian GEFs of the DH/PH family.


A prospective cohort study of cigarette smoking and pancreatic cancer in Japan.
To examine the association of cigarette smoking with the risk of death from pancreatic cancer in a prospective cohort study. A total of 110,792 inhabitants, aged 40-79 years (46,465 men and 64,327 women), were enrolled from 1988 to 1990 and followed up for mortality to the end of 1997. At baseline a self-administered questionnaire was used to obtain information on cigarette smoking and other lifestyle factors. During the follow-up period (mean +/- SD: 8.1 +/- 1.8 years), 225 deaths due to pancreatic cancer were identified. After adjustment for age, body mass index, history of diabetes mellitus, and gallbladder diseases, the relative risks (RRs) for current smokers were 1.6 (95% CI 0.95-2.6) in males, and 1.7 (95% CI: 0.84-3.3) in females. Men who smoked more than 40 cigarettes per day had a substantially higher risk of pancreatic cancer, with a RR of 3.3 (95% CI: 1.4-8.1). A significantly decreasing trend in risk with increasing years after smoking cessation was observed (trend p = 0.04) among male ex-smokers. The RRs were 0.85 (95% CI 0.36-2.0) and 0.85 (0.36-2.0) for those who had quit smoking for 10-19 and > or =20 years, respectively. Our cohort study confirmed that cigarette smoking was associated with an increased risk of death from pancreatic cancer.


1,3-Diethyl-1,3-diphenyl-urea.
The mol-ecule of the title compound, C(17)H(20)N(2)O, a symmetrical derivative of urea, shows non-crystallographic C(2) symmetry. Inter-action with the aromatic system of the phenyl substituents as well as amide-type resonance is responsible for the marked planarization of the coordination environments of the N atoms. C-H⋯O contacts give rise to the formation of centrosymmetric dimers in the crystal structure. The closest distance between the centroids of two adjacent rings is 3.8938 (11) Å.


On the mode of action of the immunosuppressive sesquiterpene ovalicin.
When the potent immunosuppressive sesquiterpene ovalicin is added to lymphocyte cultures one first observes a preferential inhibition of uridine incorporation into rRNA. The uptake of the nucleoside, its conversion into the triphosphate or the polymerizing activity itself are not affected. A longer period of incubation with the drug results in a marked decrease in the number of ribosomes, with a concomitant reduction of the rate of leucine incorporation into all cellular proteins. After extended periods of time, the incorporation of thymidine into DNA in stimulated lymphocytes as well as in SV49.1 lymphoma cells is inhibited by 1 nM ovalicin or less, although part of the incorporation seems to be resistant to the drug even at much higher concentrations. A similar affect is observed with 3T6 mouse fibroblasts or HeLa cells. Here, however, a much longer incubation with the drug is required. This observation explains the selective effect of ovalicin on lymphocytes observed in vivo.


Binding isotherms of sodium dodecyl sulfate to protein polypeptides with special reference to SDS-polyacylamide gel electrophoresis.
To clarify the mode of interaction between sodium dodecyl sulfate (SDS) and protein polypeptides with special reference to SDS-polyacrylamide gel electrophoresis, the binding of SDS to several protein polypeptides was investigated by the equilibrium dialysis technique. Each of the binding isotherms was characterized by the presence of two phases: an initial gradual increase in the amount of binding to 0.3-0.6 g/g (first phase) and a subsequent steep increase to 1.2-1.5 g/g (second phase). The binding was completed at a concentration of SDS below the critical micelle concentration. Throughout the first and second phases, the isotherms obtained were different for each kind of protein. On the basis of experiments with bovine serum albumin and ribonuclease (EC 184.108.40.206], the isotherms were profoundly affected by the method used for modification of the sulfhydryl groups. The claim of Reynolds and Tanford (Proc. Natl, Acad. Sci. U.S., 66, 1002 (1970)) that the isotherms are virtually identical for many kinds of proteins was not supported by the present data. Changes in the gross and local conformations were examined with reference to the isotherms by measurements of CD spectrum, free boundary electrophoresis, and gel filtration. The results obtained were collectively interpreted based on the model of SDS-protein polypeptide complexes proposed by the present authors (J. Biochem., 75, 309 (1974)).


Structural derivatives of pindolol: relationship between in vivo and in vitro potencies for their interaction with central beta-adrenergic receptors.
Although (-)-125I-iodopindolol (IPIN) can be used to label beta-adrenergic receptors in the central nervous system (CNS) in vivo, use of this ligand for receptor imaging studies in humans may be limited due to its relatively poor penetration into the CNS. A series of derivatives related to pindolol was therefore studied in an effort to determine the factors that might influence the penetration and interaction of these compounds with central beta-adrenergic receptors in vivo. Evaluation of the ability of these derivatives to displace the binding of IPIN in the brain upon systemic administration provides an assessment of whether the derivatives penetrate and interact with central beta-adrenergic receptors in vivo. Multiple regression analyses showed that the most important factor which influences the ability of the pindolol derivatives to penetrate into the brain and interact with beta-adrenergic receptors in vivo is the affinity of the derivatives for binding to beta-adrenergic receptors in vitro. Both lipophilicity and the molecular weights of the derivatives are important secondary factors which influence their in vivo potency.


Long-Term Effects of Ambient PM2.5 on Hypertension and Blood Pressure and Attributable Risk Among Older Chinese Adults.
Long-term exposure to ambient fine particulate pollution (PM2.5) has been associated with cardiovascular diseases. Hypertension, a major risk factor for cardiovascular diseases, has also been hypothesized to be linked to PM2.5 However, epidemiological evidence has been mixed. We examined long-term association between ambient PM2.5 and hypertension and blood pressure. We interviewed 12 665 participants aged 50 years and older and measured their blood pressures. Annual average PM2.5 concentrations were estimated for each community using satellite data. We applied 2-level logistic regression models to examine the associations and estimated hypertension burden attributable to ambient PM2.5 For each 10 μg/m3 increase in ambient PM2.5, the adjusted odds ratio of hypertension was 1.14 (95% confidence interval, 1.07-1.22). Stratified analyses found that overweight and obesity could enhance the association, and consumption of fruit was associated with lower risk. We further estimated that 11.75% (95% confidence interval, 5.82%-18.53%) of the hypertension cases (corresponding to 914, 95% confidence interval, 453-1442 cases) could be attributable to ambient PM2.5 in the study population. Findings suggest that long-term exposure to ambient PM2.5 might be an important risk factor of hypertension and is responsible for significant hypertension burden in adults in China. A higher consumption of fruit may mitigate, whereas overweight and obesity could enhance this effect.


Human ferritin H and L sequences lie on ten different chromosomes.
In humans, the H (heavy) and L (light) chains of the iron-storage protein ferritin, are derived from multigene families. We have examined the chromosomal distribution of these H and L sequences by Southern analysis of hybrid cell DNA and by chromosomal in situ hybridization. Our results show that human ferritin H genes and related sequences are found on at least seven different chromosomes while L genes and related sequences are on at least three different chromosomes. Further, we have mapped the chromosomal location of expressed genes for human H and L ferritin chains and have found an H sequence which may be a useful marker for idiopathic hemochromatosis.


Asymptomatic Common Carotid Artery Occlusion and Occipital-Vertebral Artery Anastomosis: A Case Report and Literature Review.
Common carotid artery occlusion (CCAO) is a very rare disorder that has rarely been studied. CCAO causes several neurological symptoms but can sometimes be asymptomatic due to the development of various anastomoses. Herein, we report the case of a 70-year-old male patient diagnosed with asymptomatic CCAO due to anastomotic flow. The patient underwent transfemoral cerebral angiography (TFCA) and was found to have CCAO with two collateral pathways, including an occipital artery-vertebral artery anastomosis. We emphasize the importance of TFCA when CCAO is suspected and review the types and anastomotic pathways of CCAO.


Effects of additional team-based learning on students' clinical reasoning skills: a pilot study.
In the field of Neurology good clinical reasoning skills are essential for successful diagnosing and treatment. Team-based learning (TBL), an active learning and small group instructional strategy, is a promising method for fostering these skills. The aim of this pilot study was to examine the effects of a supplementary TBL-class on students' clinical decision-making skills. Fourth- and fifth-year medical students participated in this pilot study (static-group comparison design). The non-treatment group (n = 15) did not receive any additional training beyond regular teaching in the neurology course. The treatment group (n = 11) took part in a supplementary TBL-class optimized for teaching clinical reasoning in addition to the regular teaching in the neurology course. Clinical decision making skills were assessed using a key-feature problem examination. Factual and conceptual knowledge was assessed by a multiple-choice question examination. The TBL-group performed significantly better than the non-TBL-group (p = 0.026) in the key-feature problem examination. No significant differences between the results of the multiple-choice question examination of both groups were found. In this pilot study participants of a supplementary TBL-class significantly improved clinical decision-making skills, indicating that TBL may be an appropriate method for teaching clinical decision making in neurology. Further research is needed for replication in larger groups and other clinical fields.


The effect of subcutaneous mesenchymal stem cell injection on statis zone and apoptosis in an experimental burn model.
In an acute burn injury the zone of stasis is initially vital but may progress to coagulation necrosis with time. In this study, salvage of the zone of stasis was aimed at by subcutaneous mesenchymal stem cell injection. Mesenchymal stem cells were obtained from the bone marrow of Sprague-Dawley rats (n = 10). Twenty Sprague-Dawley rats received thermal injury on the back according to the previously described "comb burn" model. Thirty minutes after the burn injury, mesenchymal stem cells were injected subcutaneously to the stasis zone of the experimental group (n = 10). Animals in the control group (n = 10) were given the same amount of saline without mesenchymal stem cells. Animals in the sham group (n = 6) did not receive any thermal trauma. Seventy-two hours after the burn injury, scintigraphic examination was applied to determine average vital tissue at the stasis zone. Thereafter, skin samples were assessed by immunohistochemistry assay for apoptosis count. The blood samples drawn before and 72 hours after the burn injury were analyzed to determine systemic cytokine levels. The apoptosis count of the control group was found to be significantly higher than that of the experimental group. Vital tissue percentage of the stasis zone was significantly higher for the experimental group than for the control group. The cytokine levels did not reveal any statistically significant difference between the groups. Apoptosis count and scintigraphic results of this study confirm that mesenchymal stem cell treatment has a statistically significant benefit for the survival of the stasis zone in acute burn.


Intramolecular cyclizations of polyketide biosynthesis: mining for a "Diels-Alderase"?
Despite the large number of naturally occurring metabolites existing for which enzymatic Diels-Alder reactions have been proposed as a key biosynthetic step, the actual number of enzymes thus far identified for these transformations is incredibly low. Even for those few enzymes identified, there is currently little biochemical or mechanistic evidence to support the label of a "Diels-Alderase." For several families of polyketide metabolites, the transformation in question introduces a rigid, cross-linked scaffold, leaving the remaining peripheral modifications and polyketide processing to provide the variation among the related metabolites. A detailed understanding of these modifications--how they are introduced and the tolerance of enzymes involved for alternate substrates--will strengthen biosynthetic engineering efforts toward related designer metabolites. This review addresses intramolecular cyclizations that appear to be consistent with enzymatic Diels-Alder transformations for which either the responsible enzyme has been identified or the respective biosynthetic gene cluster for the metabolite in question has been elucidated.


Concentration-dependent enrichment of resistant Enterococcus faecium exposed to linezolid in an in vitro dynamic model.
To explore the relationship between pharmacokinetic variables and enterococcal resistance to linezolid, a vancomycin-resistant strain whose mutant prevention concentration (MPC) exceeded the MIC by two fold was selected among six clinical isolates of Enterococcus faecium. The selected strain was exposed to simulated pharmacokinetics of twice-daily linezolid for five days. Mutants resistant to 2 × MIC of the antibiotic were enriched at ratios of the 24-h area under the concentration-time curve (AUC24) to the MIC of 15 and 30 h but not at 60 and 120 h. These observations could be explained by the different times when antibiotic concentrations exceed the MPC (T>MPC): 0 to 14, 63 and 100% of the dosing interval. Using the area under the bacterial mutant concentration-time curve (AUBCM) determined in this study and in previous work with other E. faecium strains (MPC/MIC 4), a strain-independent T>MPC relationship with mutant enrichment was established.


Catalyst-Free Regioselective C-3 Thiocyanation of Imidazopyridines.
A direct and straightforward approach for highly regioselective thiocyanation of imidazoheterocycles through sp(2) C-H functionalization has been realized at room temperature. Various C-3 thiocyanated imidazopyridines are formed in moderate to good yield. The present method exhibits a mild and selective access to a variety of imidazopyridine derivatives of pharmacological interest.


Quality control of the ambulatory polygraphy using automatic analysis.
It is necessary to ensure the quality of sleep studies conducted at home given that there can be potential variations. Automatic analysis is simple and could help in an audit. The objective is to find a predictive model of visual reading using an automatic analysis of saturation and respiratory signal in order to establish a reading standard with a polygraph used at home on patients who have sleep apnea-hypopnea clinical symptoms. The analysis was carried out using the following two definitions of hypopnea: an event with a duration of >or= 10 s with a decrease of > 30% of the respiratory signal; and an event associated either with a desaturation of >or= 3% or with a desaturation of >or= 4%. A total of 189 studies were selected from a representative sample of 218 patients. Two pneumologists carried out the readings together. The agreement between the visual respiratory disturbance index (RDI) [ie, apneas plus hypopneas] for both definitions and the automatic respiratory signal analysis (ie, automatic RDI [RDIa]) or the automatic desaturation index of 3% (DI3%a) and of 4% (DI4%a) showed limits from a Bland-Altman plot that were too large. However, a multiple linear regression analysis with RDIa and DI3%a or RDIa and DI4%a presented an acceptable level of agreement with RDI for both definitions (p < 0.001; r(2) = 96.2% and 97%, respectively). The 95% confidence interval for the differences between the RDI and the model was +/- 10.1 or +/- 8.8 events per hour, so a study should be revised outside of these limits. A predictive multiple regression model that uses the automatic analysis of the oximetry and respiratory signal could establish a standard for the visual reading of polygraphy at home.


Rehabilitation access and effectiveness for persons with back pain: the protocol of a cohort study (REHAB-BP, DRKS00011554).
Back pain is one of the most common chronic diseases in Germany and has a major impact on work ability and social participation. The German Pension Insurance (GPI) is the main provider of medical rehabilitation to improve work ability and prevent disability pensions in Germany. However, over half of the persons granted a disability pension have never used a medical rehabilitation service. Furthermore, evidence on the effects of medical rehabilitation in Germany is inconclusive. Consequently, this study has two aims: first, to determine barriers to using rehabilitation services, and second, to examine the effectiveness of medical rehabilitation in German residents with chronic back pain. In 2017 a postal questionnaire will be sent to 45,000 persons aged 45 to 59 years whose pension insurance contributions are managed by the GPI North or the GPI Central Germany. In 2019 respondents who report back pain in the first survey (n = 5760 expected) will be sent a second questionnaire. Individuals will be eligible for the first survey if they are employed, have neither used nor applied for a rehabilitation programme during the last 4 years and neither received nor applied for a disability pension. The sample will be drawn randomly from the registers of the GPI North (n = 22,500) and the GPI Central Germany (n = 22,500) and stratified by sex and duration of sickness absence benefits. Barriers to rehabilitation services will be related to socio-demographic and social characteristics, pain and attitudes to pain, health and health behaviour, healthcare utilisation, experiences and cognitions about rehabilitation services and job conditions. Propensity score matched analyses will be used to examine the effectiveness of rehabilitation services. Data on use of medical rehabilitation will be extracted from administrative records. The primary outcome is pain disability. Secondary outcomes are pain intensity and days of disability, pain self-efficacy, fear avoidance beliefs, self-rated health, depression, healthcare utilisation, self-rated work ability and subjective prognosis of employability, sickness absence benefits, and disability pensions. This study identifies barriers to use of rehabilitation services and determines the effectiveness of medical rehabilitation for patients with chronic back pain. German Clinical Trials Register ( DRKS00011554 , January 26, 2017).


Obligatory Nasal Turbulence as a Trigger for the Development of Posterior Nasal Fricatives in a Child With Repaired Cleft Palate.
Posterior nasal fricatives (PNFs) are unusual articulations that occur in some children with and without cleft palate. The etiology of PNFs is unclear. A young girl with repaired cleft palate is described who exhibited inconsistent obligatory nasal turbulence during production of stops at 2 years of age. At 3 years of age, she exhibited various phonological processes and used PNFs to replace sibilants and affricates. Pressure-flow testing showed a relatively small velopharyngeal area during production of stops. These observations are consistent with obligatory nasal turbulence triggering the development of PNFs as an unusual phonological process, perhaps facilitated by reduced hearing.


Preparation, biodistribution, and small animal PET of 45Ti-transferrin.
Investigation of 45Ti-transferrin was pursued to provide insight into the mechanism of action of titanocene dichloride, a chemotherapeutic agent currently in clinical trials. Plasma protein-binding studies of processed 45Ti were performed by solubilizing the 45Ti residue in 0.05N HCl, of which 1.22 MBq (33 microCi) in 10 microL were added to 250 microL of dog plasma. 45Ti-Transferrin was prepared by redissolving the processed 45Ti in 25 micromol/L apotransferrin or by in vivo incorporation through preparation and introduction of 45Ti-citrate. Biodistribution studies were performed on normal Sprague-Dawley rats and EMT-6 tumor-bearing BALB/c mice with 45Ti-transferrin coinjected with 67Ga-citrate for direct comparison. microPET was performed on mice bearing EMT-6 tumors and the images were analyzed for tumor-to-muscle uptake ratios. Direct labeling of apotransferrin in situ with 45Ti was achieved as well as in vivo incorporation by 2 h after injection with 45Ti-citrate. The biodistribution of 45Ti-transferrin and 67Ga-citrate showed similar trends. In Sprague-Dawley rats, initial blood uptake was higher for the 45Ti-transferrin, whereas bone uptake increased more for the 67Ga-citrate. EMT-6 tumor uptake in both cases was relatively high (14.6 +/- 1.83 %ID/g for 45Ti and 8.72 +/- 0.98 %ID/g for 67Ga [%ID/g = percentage injected dose per gram]) and remained elevated even out to 24 h after injection. The tumor-to-muscle ratio of the 67Ga-citrate reached 6.7 at 24 h, whereas the ratio of the 45Ti-transferrin increased to 4.3 at this time point. Uptake of 45Ti-transferrin was visualized in the EMT-6 murine mammary carcinoma tumor with microPET. In all cases, the tumor was clearly delineated from the surrounding tissue with tumor-to-muscle ratios on the order of 1.6. 45Ti forms a complex with apotransferrin that remains intact in vivo. Results of the biodistribution in mice showed that the tumor had increased uptake compared with nontarget organs (e.g., muscle). The microPET images of tumor-bearing mice clearly delineate the tumors from the surrounding tissue. Comparison of the data suggests that tissue uptake is similar whether injecting 45Ti-transferrin directly or as 45Ti-citrate, which transchelates to transferrin before the time of imaging.


Differences in the perceptions of HIV risk amongst dental care providers in Western Australian clinics.
This paper examines the perceived risk of occupationally contracting HIV among dental care providers. This examination is based upon responses to a mailed questionnaire from all registered dentists (76 per cent response rate, n = 550) and dental therapists (63 per cent response rate, n = 208) in Western Australia during 1992. Results indicate that: 1) dental care providers who perceive a high risk of occupationally contracting HIV report a more conservative, cautious approach to HIV infection than do providers who perceive less risk of contracting the virus; 2) dental therapists are more likely than dentists to report a higher degree of perceived risk of occupationally contracting HIV; and 3) dentists are more likely than dental therapists to perceive compliance with universal precaution guidelines in dental practices in which they work. Reasons are presented for a suspicion that both sets of perceptions may be exaggerated. The need to educate dental therapists on the realistic risks of occupationally contracting HIV and to educate dentists on the value of compliance (and of appearing to comply) with universal precaution guidelines in order to help reduce undue stress and hindrances in the provision of safe and effective dental care in this era of AIDS concludes this paper.


Sanitation options for managing oak wood infested with the invasive goldspotted oak borer (Coleoptera: Buprestidae) in southern California.
Movement of invasive wood-boring insects in wood products presents a threat to forest health and a management challenge for public and private land managers. The goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), is a new pest in San Diego and Riverside Cos., CA, believed to have been introduced on firewood. This beetle has caused elevated levels of oak mortality since 2002. From 2009-2011, we tested several sanitation methods, applicable to large and small land parcels, to reduce or prevent goldspotted oak borer emergence from infested oak wood. In most experiments, emergence of goldspotted oak borer adults from the positive controls demonstrated that the beetle could complete development in firewood-sized pieces of cut oak wood. In 2009, adult emergence from sun-exposed oak wood began and peaked 2- to 4-wks earlier at a low elevation site than at a high elevation site (late May to late June). However, there were no significant effects of elevation or host species on the emergence response of goldspotted oak borer by solarization treatment in this study. Solarization of infested wood with thick (6 mil) and thin (1 mil) plastic tarpaulins (tarps) did not significantly reduce emergence of adults despite recordings of greater mean and maximum daily temperatures in both tarped treatments and greater relative humidity in the thick-tarped treatment (all compared with nontarped controls). Grinding wood with a 3"-minus screen (< or = 7.6 cm) significantly reduced goldspotted oak borer emergence compared with control treatments, and this was the best method for reducing adult emergence among those tested. In a separate grinding study, no adults emerged when wood was ground to 9"-minus (22.9 cm), 2"-minus (5.1 cm), or 1"-minus (2.5 cm) screen sizes, but a low level of adult emergence from the positive controls limited any inferences from this experiment. Debarking cut wood pieces eliminated goldspotted oak borer emergence from the wood fraction, but adults emerged from the shaved bark and phloem.


Role of Toll-Like Receptor 2 in Regulation of T-Helper Immune Response in Chronic Obstructive Pulmonary Disease.
According to modern views, the differences in the clinical course of chronic obstructive pulmonary disease (COPD) are associated with certain types of T-helper (Th) immune response. Recent data have shown that toll-like receptor 2 (TLR2) is involved in the development of Th immune response. However, TLR2-mediated regulation of Th subpopulation balance in COPD needs to be elucidated. The aim of our work is to determine the mechanisms of TLR2-mediated regulation of Th immune response in COPD of varying severity. The study included 323 smokers/ex-smokers with stable COPD (GOLD I, GOLD II, and GOLD III) and 97 healthy nonsmokers (control group). Serum levels of Th1 (TNF-α and IFN-γ), Th2 (IL-4), Th17 (IL-6 and IL-17A), Treg (IL-10) cytokines, and the percentage of peripheral blood Th cells expressing TLR2 (CD4+CD282+) were assessed by flow cytometry. Serum concentrations of IL-21 (Th17) and TGF-β1 (Treg) were measured using the ELISA method. The predominant Th cytokine profile in serum was determined by calculating the ratios between levels of Th1 and Th17 cytokines. Spearman's correlation test was performed. Patients with COPD GOLD II and III with Th1 and Th17 cytokine profiles exhibited an increase in the percentage of CD4+CD282+ cells compared to the control group. In COPD GOLD I-III, positive correlations between CD4+CD282+ cell frequency and Th17 cytokine levels (IL-6, IL-17A, and IL-21) were found. In COPD GOLD I, IL-10 concentration was negatively correlated with the percentages of studied cells; in COPD GOLD II, a positive correlation between these parameters was noted. Enhanced TLR2 expression on CD4+ cells shifts cytokine profile toward Th17 phenotype that plays a crucial role in COPD progression. The level of TLR2 expression on peripheral blood CD4+ cells may be considered as a biomarker for diagnosing and predicting the progression of COPD.


Ethical aspects of genetic testing in the workplace.
The European Group on Ethics and New Technologies, which advises the European Commission, has published an opinion paper on ethical aspects of genetic testing in the workplace. The paper goes well beyond the usual ethical issues, presenting a summary of genetic testing in the workplace in the United States and Europe and criteria for appropriate testing. Unlike many other documents on ethics, it pays close attention to the problem of false-positive and false-negative test results. Although no genetic tests are currently appropriate for screening workers or applicants for jobs in which occupational hazards exist, inappropriate testing has occurred and regulations are needed to ensure that only appropriate testing is used in the future. Workers or their representatives should be involved in deciding when and how genetic testing in the workplace is done.


Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide.
Inhaled, long-acting beta2-agonists or antileukotrienes are alternatives as add-on therapy for asthmatic children taking regular inhaled steroids. Any complementary effects would be relevant to the choice between these alternatives. Exhaled nitric oxide (FeNO) may reflect these effects. To compare the control of FeNO provided by salmeterol or montelukast add-on therapy in asthmatic children undergoing regular maintenance treatment with a daily dose of 400 microg of budesonide. The study included children with increased FeNO despite regular treatment with budesonide, 400 microg/d, and normal lung function. Montelukast, 5 mg/d, salmeterol, 50 microg twice daily, or placebo was compared as add-on therapy to budesonide, 400 microg, in a randomized, double-blind, double-dummy, crossover study. Twenty-two children completed the trial. The geometric mean FeNO level was 20 ppb (95% confidence interval [CI], 15-27 ppb) after salmeterol, which was significantly higher than after montelukast (mean, 15 ppb; 95% CI, 11-18 ppb; P = 0.002) and placebo (mean, 15 ppb; 95% CI, 10-21 ppb; P = 0.03). There was no difference in FeNO between the montelukast and placebo groups. Mean forced expiratory volume in 1 second (FEV1) was significantly increased after salmeterol (mean, 2.63 L; 95% CI, 2.34-2.91 L) compared with placebo (mean, 2.48 L; 95% CI, 2.19-2.77 L). Montelukast (mean, 2.57 L; 95% CI, 2.33-2.80 L) was no different than placebo. The FeNO levels were significantly higher after salmeterol add-on treatment compared with both placebo and montelukast add-on treatment. Salmeterol significantly improved lung function (FEV1) compared with placebo and nonsignificantly compared with montelukast. Montelukast failed to reduce FeNO and improve lung function compared with placebo in this group of children taking regular budesonide, 400 microg.


Effect of chemodenervation on the cerebral vascular and microvascular response to hypoxia.
This study evaluated the effect of bilateral carotid chemodenervation on the cerebrovascular response to hypoxia in conscious rats. Cerebral blood flow was measured using 4-iodo[N-methyl-14C]antipyrine, and the total and perfused microvasculature was studied by injection of fluorescein isothiocyanate dextran and alkaline phosphatase staining. To maintain constant PCO2, hypoxia was achieved in chemoreceptor-intact rats by the use of 4% CO2-8% O2-88% N2 and in chemodenervated rats by the administration of 8% O2-92% N2. Blood gas and hemodynamic parameters were similar in the two groups of rats. Chemodenervation had no significant effect on either resting blood flow or the perfused microvasculature during normoxia. A significant increase in cerebral blood flow (from 71 +/- 3 to 138 +/- 9 ml/min/100 g in control and from 91 +/- 5 to 127 +/- 7 ml/min/100 g in chemodenervated rats) and in the percent of cerebral arterioles and capillaries perfused occurred in both hypoxic control and chemodenervated rats. In chemoreceptor-intact rats, the greatest increase in blood flow and in perfused microvasculature occurred in caudal structures (medulla and pons) in comparison with rostral structures (cortex, thalamus, and hypothalamus). In chemodenervated rats, a similar increase in blood flow and perfused microvasculature occurred in all brain regions, with no regional differences. Thus, chemodenervation did not affect the overall cerebral blood flow or the microvascular response to hypoxia; however, rostral-to-caudal regional differences in the hypoxic response were lost after chemodenervation.


Temperature changes in bulk-fill resin composite during photopolymerization.
To investigate the temperature changes at multiple sites within bulk-fill resin composites and in the pulp chamber during photopolymerization in the tooth cavity. Class 1 cavities (n = 5) prepared in extracted third molars were filled with SureFil SDR Flow, a newly developed bulk-fill composite. After securing the specimens in a water bath at 36.5 degrees C, eight thermocouples were used to measure the temperature at the bottom center (BC), middle center (MC), top center (TC), bottom edge (BE), middle edge (ME), and top edge (TE) of the restoration; the pulpal aspect of the dentin (PD); and the center of the curing light tip (CL) during photopolymerization. The maximum temperature values (degrees C) differed among the measurement sites. TC exhibited the greatest temperature increase (72.3 ± 2.4), followed by MC, BC, TE, TE, ME, CL, and BE. The lowest temperature was observed at PD (41.1 ± 1.9). The peak temperatures within the composite were observed during the early stage of light-curing, while CL and PD exhibited the highest temperature at the end stage of light-curing.


Does smoking reduce the progression of osteoarthritis? Meta-analysis of observational studies.
To determine whether smoking reduces the progression of osteoarthritis (OA). Observational studies examining smoking and progression of OA were systematically searched through Medline (1948-), EMBase (1980-), Web of Science, PubMed, and Google and relevant references. The search was last updated in May 2012. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were directly retrieved or calculated. Current standards for reporting meta-analyses of observational studies (Meta-Analysis of Observational Studies in Epidemiology) were followed. Quality-related aspects such as study design, setting, sample selection, definition of progression, and confounding bias were recorded. Stratified and meta-regression analyses were undertaken to examine the covariates. Sixteen studies (976,564 participants) were identified from the literature. Overall, there was no significant association between smoking and progression of OA (OR 0.92; 95% CI 0.83, 1.02). There was moderate heterogeneity of results (I(2) = 57.3%, P = 0.0024). Subgroup analyses showed some associations of marginal significance; however, meta-regression did not confirm any significant results. There is no compelling evidence that smoking has a protective effect on the progression of OA. The results concur with a previous meta-analysis published by this group that showed no association between smoking and incidence of OA. Taken together, smoking does not appear to reduce either the incidence or progression of OA.


The impact of metabolism on DNA methylation.
Methylation of genomic cytosines is one of the best characterized epigenetic mechanisms, and investigation of its relationship with other biochemical pathways represents a critical stage in the elucidation of biological information processing. The field also has immense potential for the development of medical treatments for any number of conditions ranging from aging to neurological disorders. The DNA methylation status of genes is responsible for many heritable traits and varies more or less independently of the genetic code. This variation is often a result of cellular environmental factors including metabolism. A key metabolite in this regard is homocysteine. Knowledge of homocysteine metabolism continues to be amassed, yet the part played by aberrant DNA methylation in homocysteine-related pathologies is often, at best, conjectural. In this analysis, we will review recent insights and attempt to speculate meaningfully concerning the dynamics of the methionine cycle in relation to DNA methylation and disease.